update of prognostic and predictive biomarkers in oropharyngeal ... · 20-03-2012 · 6 eur arch...

Eur Arch Otorhinolaryngol (2011) 268:5–16
DOI 10.1007/s00405-010-1369-x
REVIEW ARTICLE

Update of prognostic and predictive biomarkers in oropharyngeal squamous cell carcinoma: a review

Carolin M. Grimminger · Peter V. Danenberg

Received: 23 June 2010 / Accepted: 12 August 2010 / Published online: 9 September 2010© Springer-Verlag 2010

Abstract Oropharyngeal squamous cell carcinomas(OSCC) constitute about 5% of all cancers in the westernworld and the incidence and mortality rates of this tumorhave shown little improvement over the last 30 years.Molecular targeted therapy, a promising strategy for thetreatment of OSCC and other cancers, requires the under-standing of speciWc molecular events of carcinogenesis andthe diVerent pathological, partly interrelated pathways.Extended knowledge of the prognostic or predictive valueof molecular biomarkers in oropharyngeal cancer is neces-sary to allow a better characterization and classiWcation ofthe tumor, improve the appraisal of clinical outcome andhelp to specify individual multimodal therapy withincreased eYciency. This work aVords an updated sum-mary regarding recent data about tissue biomarkers inpatients with OSCC, based on the six essential hallmarks ofcancer described by Hanahan and Weinberg (Cell100(1):57–70, 2000) providing the characterization of amalignant cell.

Keywords OSCC · Predictive and prognostic biomarker · Hallmarks of cancer · HPV

Introduction

Each year in the USA, about 35,700 new cases of oral cav-ity and oropharyngeal cancer are reported and an estimated7,600 people die of these diseases [46].Oropharyngealsquamous cell carcinomas (OSCC) constitute about 5% ofall cancers in the western world and the incidence and mor-tality rates of this cancer have shown little improvementover the last 30 years [46, 105]. Histopathologically, squa-mous cell carcinoma is by far the most common cancer typeof the oropharynx and oral cavity, representing more than90% of all oral cancers. Despite the improved applicationof multimodal therapy, the survival rate of patients suVer-ing frequently from locoregional and distant recurrences ispoor and highlights the need for new approaches concern-ing early diagnosis and treatment alternatives [15].

Human papilloma virus in OSCC

Previous molecular biological and epidemiological studiesdivided OSCC into two biologically diVerent tumor enti-ties, presenting themselves at the same location and withsimilar histology [113]. Besides a patient’s genetic predis-position, it was established that a big part of the etiology ofthese tumors is related to the consumption of alcohol andnicotine [13]. However, one-third of the patients repre-sented a group that does not feature these risk factors buttested positive for oncogenic human papilloma virus [90].Human papilloma viruses (HPV) are small DNA virusescausing mainly benign growth, known as papillomas orwarts, but the infection with high-risk-types (HR-HPV),basically mucotrop HPV type 16 and 18, were found to berisk factors for carcinogenic degeneration and led to thedevelopment of cancer after years of latency. This pathwayis found in a range of carcinomas, e.g., cervical carcinoma,

C. M. Grimminger · P. V. DanenbergDepartment of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA

C. M. Grimminger (&)Department of Otorhinolaryngology and Head and Neck Surgery, University Hospital of Cologne, 50931 Cologne, Kerpenerstr 62, 50924 Köln, Germanye-mail: [email protected]

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vulva, penis and anal carcinoma, as well as oropharyngealtumors [22, 36]. These tumors are distinguished from toxin-induced OSCC in multiple biological aspects, includingspeciWc molecular and genetic alterations.

The high prevalence of HPV in oropharyngeal carcino-mas relates mainly to carcinomas of the tonsils and thetongue base. This might be explainable by their typicalcryptic epithelium, which serves as a virus-reservoir. Also,the one- to two-layered cryptic epithelium provides an eas-ier infection of the basal membrane [3]. Further explana-tions are possible diVerences in cell diVerentiation and localinterleukin expression [53, 56]. Other tumor locations ofthe upper aero-digestive mucosa could cause a considerablevariation of the prevalence of HPV positivity. Clinically,HPV-positive (HPV+) tumors are characterized by a morefavorable prognosis, possibly a result of better response tochemotherapy and radiotherapy due to their distinct biolog-ical behavior. It is known that there are considerablegenetic aberrations between the two tumor entities [35]: forexample, variations of expression of diVerent cell cycleproteins, e.g., p16, and also EGFR or survivin [13]. ThesediVerent molecular signatures should be unraveled so as togain more knowledge for future tailored therapies depen-dent on the HPV status of the tumor.

Molecular alterations in OSCC

The development and malignant progression of OSCCprobably is rarely if ever due to a single dysfunctional geneor pathway. Multiple genetic alterations accumulate duringcarcinogenesis, involving multiple pathways and down-stream genes that have important functions in determiningthe malignant phenotypes of cancer [37, 55]. In toxin-induced OSCC, carcinogenesis appears to be generated viaaccumulation of numerous distinct genetic and epigeneticchanges. Early common changes are deletions on chromo-some 3p and 9p21, which have also been found in prema-lignant lesions [76]. Loss of heterozygosity (LOH) ofchromosome 17p, mutation of the p53 gene, ampliWcationof 11q13 and overexpression of cyclin D1 occur in furtherstages of carcinogenesis of head and neck squamous cellcarcinoma (HNSCC).

Molecular biomarkers (OSCC)

The eVects of multimodal therapy on OSCC tumors vary, butoverall more than 50% of multimodally treated patients expe-rience recurrence and the 5-year survival rate of OSCC is notincreased by more than 40–50% [40]. It has been noted in theearly 1980s that chemosensitive tumors are also likely to beradiosensitive[28] Therefore, induction chemotherapy canhelp to select patients who are good candidates for radiother-

apy and allows early surgery to be performed in cases ofinsuYcient response. Reasons for these varying responsesare suspected to be the result of diVerences in the genetic sig-nature of the otherwise clinically similar tumors [33, 65].Other selection methods such as molecular biological proWlescapable of predicting sensitivity to diVerent therapeuticapproaches can not only be time and money saving, but also,more importantly, increase survival. Molecular markerscould help to characterize a malignant disease, improve theunderstanding of variations in the clinical course of individ-ual patients and estimate or even inXuence the prognosis.

Molecular targeted therapy, a promising strategy for thetreatment of OSCC and other cancers, requires understand-ing of the speciWc molecular events of carcinogenesis andthe diVerent pathological pathways. The amount of litera-ture on molecular markers and potential targets of solidtumors is enormous, but there is still a crucial need for prog-nostic or predictive markers in OSCC to allow an individualand therefore more eVective treatment. The aim of thisreview is to present an updated summary regarding tissuebiomarkers of OSCC, based on the six essential hallmarks ofcancer described by Hanahan and Weinberg [42] that pro-vides the characterization of a malignant cell (Fig. 1).

Self-suYcient growth-stimulatory signalling

In a normal cell, proliferation needs to be regulated bygrowth signals mediated by soluble and membrane-boundinteractions of diVerent signalling proteins. The process ofcarcinogenesis results from a deregulated, autonomousgrowth signalling due to gene ampliWcations, mutations,and imbalances of the level of growth factor receptors andtheir ligands or autocrine stimulation.

EGFR/HER-2/neu

Epidermal growth factor receptor (EGFR) is a membrane-bound receptor tyrosine kinase that regulates many cellularfunctions, including cellular proliferation, diVerentiationand survival. Normally, EGFR is expressed at low levels onthe surface of most cells. Deviant EGFR signalling is ahallmark of carcinogenesis.

There are four receptor types distinguishable: HER1(human epidermal growth factor receptor 1) or ErbB1,HER-2 (ErbB-2 or the HER-2/neu protooncogene), HER-3(ErbB3) and HER-4 (ErbB4) [45]. Increase or alteration inErbB1 and ErbB2 are found in many diVerent cancers, e.g.,breast, gastrointestinal, kidney, prostate and lung tumors[97]. After binding their natural ligands, such as EGF andTGF-a, these receptors autophosphorylate, resulting in mul-tiple intracellular signalling cascades, including RAS-RAF-MAPK activity, PI3K/AKT, mTOR, Jak and STAT-pathways,

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Eur Arch Otorhinolaryngol (2011) 268:5–16 7

thus highlighting the central role of EGFR in signal net-working with diVerent other oncogenes in cancers [96]. Theoverwhelming majority (90–100%) of all HNSCC presentwith EGFR overexpression, which is an independent prog-nostic marker that correlates with worse prognosis,advanced tumor stage and poor treatment outcome [88, 94].

Concerning the HPV status of a tumor, it has beenshown that HPV+/p16+ tumors tend to have decreasedEGFR expression and a signiWcantly better prognosisregarding disease-free survival (DFS) as well as overallsurvival (OS) [93]. Overexpression of EGFR ligands isoccasionally found in OSCC and is associated with poorprognosis [123].

Accordingly, various approaches to inhibit EGFR path-way in squamous cell carcinoma (SCC) have beenexplored, including small molecule tyrosine kinase inhibi-tors (TKIs) of the cytosolic kinase domain and monoclonalantibodies (mAbs) for the extracellular portions of EGFR[5, 94, 107].

Her2/neu is a well-known epithelial proto-oncogenewith sequence homology to EGFR. In gastrointestinal can-cers, HER2/neu expression showed convergence with thestage of disease and was inversely correlated with the prog-nosis of the patients [87]. Cavalot et al. [17] reported thatHER-2/neu overexpression was signiWcantly more frequentin lymph node-positive HNSCC patients and in those withcapsule rupture and vascular embolization. This Wndingunderlines the important role of HER-2/neu in supportingneoplastic growth and tumor recurrence in HNSCC. Inaddition, Cavalot et al. showed that HER-2/neu expressionand lymph node positivity were the only independent indi-cators for predicting risk of recurrence (DFS). Their report

diVers with other studies that showed no correlationbetween HER-2/neu and the clinical outcome [34, 106].Discrepancies among studies that use immunohistochemis-try (IHC) might be explained by the use of diVerent anti-bodies, diVerent interpretation of the signiWcance ofcytoplasmic staining and the lack of standardized assays.

The role of HER-4 in cancer development is still notclariWed, although there have been recent investigationsshowing that overexpression of HER-4 in breast cancermight be associated with more diVerentiated histology anda favorable clinical outcome [48, 127]. Studies by Sheuet al. [104] revealed a decreased gene copy number andexpression level of HER-4 in OSCC. Accordingly, furtherinvestigations are necessary to declare the possible tumor-suppressing function of HER-4.

Cyclin D1

Cyclin D1 (CCND1) is a proto-oncogene and key regulatorprotein in the transition from G1 to S phase of the cell cycle[103]. Positively regulated by PIN 1, it increases phosphor-ylation of the retinoblastoma gene (Rb) and thereby inducesthe S phase in cells. CCND1 gene ampliWcation is known tobe an early event in oral carcinogenesis. Overexpression ofCCND1 occurs in 25–75% of oral cancer and is a poorprognostic factor [78, 79]. Interestingly, in HPV-/p16-posi-tive OSCC, CCND1 is found to be downregulated after theinactivation of p53 and pRB by HPV-derived oncoproteinsE6 and E7. Conversely, in HPV-negative (HPV¡) tumors,increased expression levels of CCND1 were found, possi-bly due to CCND1 gene ampliWcation, which is associatedwith worse prognosis [41, 68].

Fig. 1 Samples of predictive and prognostic biomarkers in oropharyngeal carcinoma according to the six hallmarks of cancer (modiWed from Hanahan and Weinberg (2000) The hallmarks of cancer. Cell 100(1):57–70)

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Ras gene

The ras gene family includes proto-oncogenes that areknown to participate in cell growth regulation, signaltransduction and migration. The members of the humanras oncogene family are H-ras, K-ras and N-ras [7]. Theras and PI3K-AKT signalling pathways play an impor-tant role in carcinogenesis and maintenance of tumorgrowth, including decreasing the expression of tumorsuppressor genes such as p16. RAS–RAF–MAPK cas-cades are especially active when cancer cells overexpressEGFR, highlighting the critical roles of signal network-ing among diVerent oncogenes in cancers [95]. Hence,targeting ras gene products for cancer treatment is ofgreat interest. Approximately, 30% of all human cancersshow mutated ras alleles, mostly associated with poorclinical outcome and limited therapeutic options,presenting therefore the most frequently mutated onco-gene known [7, 19].

In OSCC, H-ras mutations are mainly detected in Asianpopulations, often associated with advanced stages of thetumor [23, 81]. In Western populations, ras mutations inHNSCC are relatively rare events (<6%) compared to 99%in pancreatic cancer and approximately 40% in colorectalcancer [98, 118, 122]. This diVerence might be due to theirdiVerent histological classiWcation, but has to be furtherinvestigated.

PI3K/NF-kB

Phosphoinositol 3-kinase (PI3K) is a heterodimeric lipidkinase, consisting of regulatory subunit p85 and catalyticsubunit p110� (PIK3CA), which regulate cellular signal-ling pathways including cell proliferation, diVerentiation,adhesion and apoptosis [21]. PI3K can be activated byreceptor tyrosine kinases (RTKs), such as EGFR or insu-lin receptor. Direct positive control is also possible viaactive ras. PTEN, a tumor suppressor, antagonizes PI3K[119]. It has been shown, that PI3KCA is mutated in over25% of diVerent human cancers, including gastrointesti-nal, breast, diVerent brain and head and neck cancer [100].Studies regarding the correlation of PI3K mutations andclinicopathological data in OSCC are still required. Viaphosphorylation, PI3K induces plasmaproteins in the cellmembrane, for example AKT. Activated AKT supportscell survival by inhibiting apoptosis and by activatingnuclear factor-kappa B (NF-kB). NF-kB is a ubiquitousnuclear transcription factor known to be involved ininXammation and immunoregulation. It is capable ofinhibiting apoptosis through the induction of anti-apopto-tic proteins, but can also lead to chemoresistance by sup-pressing the apoptotic potential of some anticancer agents[83].

STAT3

Signal transducers and activators of transcription (STATs)are cytoplasmic transcription factors relevant in solidtumors. After being activated via extracellular signals,STATs translocate to the nucleus, thereupon regulating thetranscription of diVerent target genes involved in cell pro-liferation, diVerentiation and apoptosis: all potential activa-tors of oncogenesis [11]. Mutation of STAT3 can lead tomalignant transformation by ampliWed po(sitive activationof downstream pathways, such as the antiapoptotic proteinsBcl-2 and Bcl-xL [64].

Previous studies revealed increased levels of activatedSTAT3 in diVerent human cancers, including HNSCC [16].Masuda et al. [77] examined 51 samples of patients withOSCC and revealed a correlation of high STAT3 expres-sion with poor diVerentiation of the tumor, lymph nodemetastasis and low survival. At the moment, investigationsconcerning the association between STAT3 expression,HPV subdivision of OSCC specimen and clinicopathologi-cal data are still pending.

Abnormality in anti-growth signals

Insensitivity of tumor cells to anti-growth signals is mainlyachieved through inactivation of tumor-suppressor genesvia diVerent mechanisms, including mutation, deletion orpromoter hypermethylation. An important part of the regu-lation of growth-inhibitory signals is taken by cyclin-dependent kinases (CDK), cyclin, the RB gene and thetumor suppressor genes p16, p21, p53 and p15.

P16 INK4A

P16 INK4A is a tumor suppressor gene located on chromo-some 9p21-22 and inhibits phosphorylation of E2F–retino-blastoma complex via binding regulatory cyclin-dependentkinases CDK4 and CDK6 [2]. Phosphorylated Rb (pRb)releases transcription factor E2F, which activates transitionof G1 to the S-phase of the cell cycle. P16 INK4A therebyregulates the cell cycle negatively, but can be suppressedby pRb itself [2, 102]. Since E7, a viral regulatory gene ofhigh-risk human papilloma virus (HR-HPV) is capable ofinactivating pRb, the repression by pRb of p16 INK4A istherefore missing, which in turn leads to an increaseddetection of p16 protein in HPV aVected cells [126]. Multi-ple studies signiWcantly demonstrated p16 INK4A as a sur-rogate marker for HPV-induced carcinoma [54, 93]. Incontrast, tumor suppressor gene p16 is found to be inacti-vated in many other malignant tumors. This includes toxic-induced head and neck carcinomas, in which p16 INK4Ainactivation via promoter hypermethylation is apparently

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an early event in carcinogenesis [76]. P16 INK4A wasrevealed as a reliable prognostic marker, even better thandirect HPV DNA analyses via PCR. A study of patientswith p16 INK4A-positive tumors showed a signiWcant bet-ter DFS, compared with p16-negative tumors [54]. Kreimeret al. [58] demonstrated that in rare cases of HPV positivityand p16 INK4A negativity, the aVected patients were heavysmokers, which could explain the inactivation of p16INK4A in these cases. Therefore, a combination of p16immunohistochemistry and HPV DNA veriWcation viaPCR is currently recommended for the identiWcation ofHPV-induced oropharyngeal carcinomas [108].

P53

P53 normally regulates cell cycle progression, cellulardiVerentiation, DNA repair and apoptosis, and is mutated in50% of all cancers. Following DNA damage, the p53 levelincreases and causes cell cycle arrest or apoptosis, depend-ing on the cell’s ability to self-repair. These reactions canbe achieved via p53 induction of kinase inhibitors, whichdecreases the phosphorylation of Rb. This leads to a largeramount of bound and, therefore, inactive E2F, therebydecreasing initiation of S-phase in cells [66]. Loss of p53function during carcinogenesis can lead to inappropriatecell growth, increased cell survival and genetic instability[12]. P53 is known to block survivin expression by arrest-ing its promoter. Hence, blockage of p53 in oropharyngealtumors causes overexpression of survivin due to absence ofinhibition [52]. Khan et al. [52] showed a frequent overex-pression of survivin and mutated p53 in OSCC as well as inoral premalignant lesions. Alteration and overexpression ofthese markers in premalignant lesions suggest a role inearly stages of oral carcinogenesis [52].

It was shown that HPV+ and HPV¡ tumors are separa-ble into two diVerent biological tumor entities. ReXectingthe diVerent steps of carcinogenesis, tobacco and alcohol-induced tumors commonly show p53 mutations as well asp16 alterations, whereas HPV+ tumors present frequentlywith a p53 wild type. In the latter case, p53 interacts withthe viral E6 protein, which leads to increased ubiquitin-dependent proteolysis of p53. Nevertheless, HPV+ tumorsare known to have a favorable prognosis, possibly as aresult of less frequent p53 mutations. P53 mutations areassociated with Weld cancerization and therefore correlatewith early recurrence and second primary tumors, as well asworse responses to chemotherapy or radiation therapy [82,93, 116].

P21

P21 belongs to the group of cyclin-dependent kinase inhibi-tors that play an essential role in cell cycle control, cellular

growth, diVerentiation and apoptosis. Cell damage stimu-lates p53 activation, which can cause increased p21 expres-sion and interaction with cyclin/CDK, leading to either cellcycle arrest or apoptosis [131]. In cases of high p21 expres-sion, an improved clinical response to chemotherapy andirradiation was reported by various authors in diVerenttypes of solid tumors [49, 121, 129]. Several studiesrevealed that a positive expression of p21 was associatedwith increased survival dates and, therefore, p21 might rep-resent a predictive marker for response of radiochemother-apy and prognosis in OSCC and other solid tumors [32,130]. Hafkamp et al. examined 77 oropharyngeal tumorsspecimens and found that in the 35% of these tumors thatwere tested HPV positive, there was a strong associationwith p21 (Cip1/WAF1) expression. P21 overexpressionseems to be a signiWcant prognosticator for a favorableprognosis [41].

Evasion of apoptosis

Malignancies are characterized by increased survival andresistance to apoptosis. Apoptosis belongs to the essentialcellular regulation processes and contains a number ofimportant components, including the family of caspases.These cysteine proteases regulate the initiation and accom-plishment of programmed cell death in altered and con-sumed cells that constitute danger to the multicellularorganism. Caspases induce proteolysis of important pro-teins, Wnally causing dissolution of the nucleus with DNAdegradation and alterations of the cell membrane [75]. P53is activated by extrinsic or intrinsic damage of the cell andis involved in regulations of the apoptotic cascade. Sincep53 is often found mutated in tumor cells, it partly explainsdecreased apoptosis in malignancies [91]. The Bcl-2 familyis also a group of apoptosis-regulatory factors. They can beclassiWed into pro-apoptotic proteins, (Bax and Bak) andanti-apoptotic proteins (Bcl-2 and Bcl-xL). Alterations ormutations of their expression as well as disequilibrium oftheir ratio can lead to deterioration of the cell [124].

Bcl-2, Bax

Bcl-2, which stands for B-cell-lymphoma-2, plays animportant role in the regulation of apoptosis and prolongedcell survival [59] and has been linked to prognosis in sev-eral solid tumors [39]. In a study by Zhang et al. [134] ana-lyzing the expression of Bcl-2 and Bax proteins via IHC inspecimens from 110 patients with OSCC, the ratio of Bcl-2/Bax was found to be an independent marker of prognosis.Camisasca et al. [14] demonstrated in 53 OSCC patientstreated with curative surgery at a single institution that theexpression of Bcl-2 family proteins was strongly associated

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with the clinical outcome of those patients. Similar resultscould be revealed by Lo Muzio et al. [70] suggesting thatdecreased Bcl-2 expression represents a more aggressivebiological behavior in OSCC. Wilson et al. examined thehistological material from 400 patients via IHC staining.Their results showed an association between Bcl-2, histo-logical dediVerentiation and a more advanced disease, butyet a lower locoregional recurrence rate and an improvedsurvival [125].

Survivin

Survivin is a member of the inhibitor of apoptosis family(IAP) and a regulator of cell division. Five diVerent splicingvariants are known so far. Survivin is rarely detectable innormal diVerentiated tissue, but highly expressed in most ofhuman malignant lesions [132].

It binds and disables caspase-3 and caspase-7, both impor-tant enzymes of the apoptosis process, thereby enabling inhi-bition of apoptosis in the cell. Survivin is frequentlyexpressed in OSCC and its expression has been reported tocorrelate with worse prognosis, disseminated disease andresistance to therapy [1]. Interestingly, there seems to be aconnection between survivin expression and the detection ofoncogenic HPV in OSCC [69]. It is already known that thereis convergence between survivin expression and increase ofdysplasia at the cervix, a disease that is also linked to HR-HPV infection [6, 9]. Preuss et al. [89] demonstrated a sig-niWcantly inverse association between cytoplasmic survivinexpression and HPV-associated OSCC. The localization ofsurvivin was found to be dynamic, since IHC showed cyto-plasmic as well as nuclear positivity, the latter possibly pre-senting the participation of survivin in controlling cellproliferation [67]. HR-HPV-correlated oncogenesis seems toinXuence active nuclear import of survivin, since a nuclearexpression of survivin, which is associated with poor OS,was signiWcantly found in HPV tumors [89]. Due to its cru-cial role in carcinogenesis, its absence in normal tissue andpotential possibilities as a molecular target, survivin has nota-ble therapeutic and prognostic interest.

ERCC1

In a broad sense, avoidance of apoptosis can be achieved byincreased DNA repair processes. Platinum chemotherapeu-tic agents are used against many diVerent cancers, especiallygerm cell tumors, ovarian, cervical and bladder cancer,small cell and non-small cell lung cancer, colorectal cancerand head and neck cancer [63]. Platinum based chemother-apy induces apoptosis by forming DNA adducts, whichleads to inter- and intrastrand cross-linking. Limitations ofthe eYciency of platinum chemotherapeutics are based onthe development of resistance. The nucleotide excision

repair pathway (NER) is an important feature to recognizeand remove DNA cross-links [92]. After excision of themodiWed DNA nucleotides, DNA polymerase restores themissing parts [44]. The excision repair cross-complementa-tion group 1 (ERCC1) is a crucial enzyme involved in theNER pathway. Interestingly, alterations in DNA damagerepair proteins can cause chemotherapeutic treatment failureand continued viability of tumor cells in many human can-cers [80]. The determination of parameters to identifypatients who would beneWt from a platinum based chemo-therapy regimen is an important goal. Analysis of ERCC1expression levels in diVerent tumors, including gastrointesti-nal [8], ovarian and lung cancer [71], exposed an inversecorrelation to treatment response and survival outcome.

Olaussen et al. examined 761 metastatic lung cancerspecimen immunohistochemically. They reported a signiW-cant survival beneWt in patients with low ERCC1 levelswho were treated with platinum chemotherapeutic agents,compared to their counterparts with increased ERCC1expression [84]. Recently, a prospective randomized trial of444 patients with progressed non-small cell lung cancer,using ERCC1 expression to assign platinum-based chemo-therapy, was performed. It was shown that ERCC1 mRNAexpression levels could signiWcantly help to predict theresponse to docetaxel and cisplatin chemotherapy, althoughthe survival rates were not signiWcantly diVerent [20].

In HNSCC, relatively few studies have been carried outto evaluate the role of ERCC1 expression as a predictivemarker. Jun et al. examined 45 patients with locallyadvanced HNSCC who received concurrent cisplatin-basedchemotherapy. Their results supported an inverse associa-tion of ERCC1 expression and prolonged survival [47].Another study showed concordance with Jun’s results byanalyzing 96 patients who underwent an induction chemo-therapy regimen for progressed HNSCC via IHC [43]. Arecent study by Koh et al. reports contrary results. Theyexamined 85 specimens of patients with HNSCC receivingplatinum-containing induction chemotherapy via IHC.ERCC1 expression did not correlate with treatmentresponse or prognosis in their retrospective setting [57].Further investigations to approve the clinical relevance ofERCC1 expression as a predictor of treatment response inoropharyngeal or other head and neck carcinomas are there-fore still necessary.

Immortalization

A normal cell can replicate itself limited by the length of itstelomeres, which aVect the life span of a cell. Telomerase isan enzyme that can elongate telomeric DNA by reversetranscription. hTERT, which stands for human telomerasereverse transcriptase, is a subunit of the telomerase, which

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is found to be increased in over 90% of all cancers. Expres-sion of hTERT enables a malignant cell to escape limitedreplication and become immortal [111, 120]. Recent studiesrevealed that hTERT expression in OSCC correlates withprognostic values. Chen et al. for example, examined 82specimens of OSCC, 116 specimens of oral epithelialdysplasia and 21 specimens of normal oral mucosa viaimmunohistochemistry. They demonstrated that hTERTexpression was an early event in oral carcinogenesis andsigniWcantly associated with the progression, recurrenceand prognosis of OSCC in Taiwan [18].

Angiogenesis

SuYcient blood supply is an important factor enabling amalignant tumor to self-maintain and grow. Therefore, pro-angiogenetic factors play an important role in the regulationof pathological angiogenesis and metastasis [42].

VEGF

VEGF is not only responsible for increased angiogenesis,but stimulates also vessel permeability, endothelial cellgrowth and proliferation. There are six diVerent VEGFfamily members diVerentiable (placental growth factor,VEGF A–E) and three VEGF receptors (VEGFR 1–3).VEGF and other angiogenic mediators, such as basic Wbro-blast growth factor (b-FGF), transmit their signal by bind-ing tyrosine kinase receptors on the cell surface [31].

At the time of diagnosis, oropharyngeal cancers mainlypresent in advanced tumor stages, already exhibiting posi-tive regional lymph nodes. VEGF-C and -D and VEGFR-3are known to be involved in lymphangiongenesis signallingpathway, therefore presenting an interesting target for can-cer therapy [74, 112]. There are contradictory Wndings con-cerning VEGF expression in OSCC and its prognosticvalue. Sappayatosok et al. examined 66 OSCC paraYn-embedded specimens with IHC regarding their expressionof pro-inXammatory and angiogenetic proteins, includingVEGF and COX-2. They demonstrated a correlation ofVEGF with tumor grading, tumor staging and angiogenesis.[101]. A study by Smith et al. of 77 patients with OSCCtreated with surgery and postoperative radiotherapyrevealed increased VEGF expression as the most signiWcantpredictor of poor disease-free and overall survival withimportant prognostic value [109]. Tanigaki et al. studiedthe expression of VEGF-A and -C, and VEGRF- 1 and - 3in 73 patients with OSCC by IHC. Multivariate analysisdemonstrated that lymph node metastasis and VEGF-Cexpression were exclusive, independent factors inXuencingthe overall survival rate and correlated with locoregionalrecurrence and distant failure [115]. However, Salven et al.

[99] examined 156 specimens of OSCC patients treatedwith multimodal therapy and reported no correlationbetween VEGF expression and QS. The latter results havebeen conWrmed by Brocic et al., who also rejected VEGF asa clinical parameter for prognosis and outcome [10]. Feiet al. [30] analyzed 85 SCC of the tonsil and could notreveal any associations between VEGF and HPV status,gender, patient age, TNM stage or EGFR expression either.

COX-2

Cyclooxygenase-2 (COX-2) is a proinXammatory enzymethat takes part in the conversion of arachidonic acid to pros-taglandins and thromboxanes, and participates in cell pro-liferation, tumor angiogenesis and apoptosis. Unlike theother isoform COX-1, COX-2 is commonly not present innormal tissue, but has an increased expression in severalhuman cancers, including OSCC [38, 118]. COX-2 synthe-sis is stimulated during inXammatory events by cytokinesand growth factors, but can be also regulated by tumor pro-moters and transcription factors.

In esophageal carcinoma, Takatori et al. [114] demon-strated in 228 patients a positive correlation between anincreased COX-2 expression and the depth of tumor inva-sion, tumor stage and prognosis. In OSCC, Sappayatosoket al. [101] examined 66 OSCC samples and found an asso-ciation of COX-2 expression with the degree of dysplasiaas well as the lymph node status, but no signiWcant correla-tion with tumor grading, staging or survival. Pannone et al.demonstrated in 22 patients with OSCC via real-time RT-PCR that a high COX-2 expression was associated with aworse DFS. A correlation with QS, tumor stage and gradecould not be shown [85]. At this time, studies analyzing therelation of HPV status, COX-2 expression and clinicopath-ological parameters in OSCC still have not been done. Incolorectal malignancies, around 80% show increased COX-2 expression, which presumably enhances tumor prolifera-tion, angiogenesis and metastasis. The chemopreventiveeVect of NSAID in colorectal cancer, including the treat-ment of familial adenomatous polyposis (FAP), has beenalready established [110].

Nonsteroidal anti-inXammatory drugs, especially selectiveCOX-2-inhibitors present an important possibility of pre-venting and targeting several cancers in early and progressedstages, despite the cardiovascular risk that has been reported.

Invasion and metastasis

Cadherins

The capability of malignant cells to inWltrate surroundingtissue diVerentiates them from normal cells. Cell–cell and

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cell–matrix interactions are important regulators for normalcellular functioning. There are diVerent specialized mole-cules and their corresponding receptors, including cadher-ins and the associated catenins. Cadherins are cell adhesionmolecules that play a signiWcant role in maintaining epithe-lial integrity, as wll as epithelial–mesenchymal transition[117]. Alterations in E-cadherin expression or their subcel-lular location are a well-known step of carcinogenesis.Inactivation of E-cadherin can be accomplished by pro-moter hypermethylation and inhibition of transcription viarepressors such as Snail, Slug or SIP1 [24, 86]. A lowexpression of E-cadherin is associated with increasedmotility, invasion and metastasis of tumor cells [4]. Diniz-Freitas et al. assessed 47 cases of OSCC to judge the rela-tion of E-cadherin expression and clinicopathologicalparameters by using IHC. Their results showed that less orabsent E-cadherin expression correlated with more invasivetumor characteristics, positive cervical lymph nodes andworse prognosis concerning disease-free and overall-sur-vival time [27]. Kaur et al. [50] conWrmed these results in astudy of 37 OSCC samples and 10 metastasized cervicallymph nodes. On the contrary, Mahomed et al. [73] whoexamined 30 cases of OSCC, partly with nodal metastasis,reported that a weak expression of E-cadherin and its asso-ciated protein, beta-catenin, correlated with a lower degreeof diVerentiation but did not show signiWcant associationwith nodal metastasis.

Matrix metalloproteinases

Matrix metalloproteinases (MMPs) are extracellular prote-ases, capable of destroying the surroundings of a tumor celland allowing tumor invasion and metastasis. The family ofMMPs contains diVerent members, distinguishable into col-lagenases, gelatinases, stromelysins, membrane-typeMMPs and new MMPs [61].

Oropharyngeal cancer is known to spread quickly in itslocoregional surrounding and 50% of the patients presentwith regional metastasis at the time of diagnosis. SeveraldiVerent MMPs, such as MMP-2, -3,-10 and -11, have beenreported to take part in the progression of oral cancer [60].MMP-2 expression was found to have predictive value con-cerning tumor metastasis in oral carcinomas [51]. Kusuk-awa et al. [62] revealed in 65 patients with stage I and II oforal carcinoma that an increased expression of MMP-3 isassociated with tumor size, thickness, mode of invasion andlymph node metastasis. Lü et al. examined MMP-1 mRNAexpression of 30 OSCC patients in paired tumor and non-tumor specimens via RT-PCR. They found high MMP-1mRNA expression to be associated with advanced tumorstages and positive cervical lymph node invasion and,therefore, reasoned MMP-1 as a potential biomarker fordiagnostic and prognostic evaluation of OSCC [72].

Yorioka et al. examined 44 samples of primary OSCC.Their techniques included microdissection and measure-ment of the activity of secreted MMPs via gelatin zymogra-phy and densitometry. Yorioka et al. [133] revealed anincreased activity of MMP-2 and -9, which correlated witha shorter DFS.

Tissue inhibitors of metalloproteinase (TIMP) are antag-onists of MMPs, but unexpectedly show a poor prognosticeVect. They can suppress angiogenesis, tumor invasion andmetastasis in vivo, but especially TIMP-2 seems to have adual function and is capable of activating MMP-2 and inde-pendently regulating cell growth and survival [26]. A studyof TIMP expression in OSCC by De Vicente et al. [25]revealed that TIMP-2 expression correlated signiWcantlywith tumor stage, local recurrence and survival outcome,while TIMP-1 showed no relation to clinicopathologicalparameters. A complete understanding of the pathophysio-logical features of MMPs and TIMPs is still lacking. Ourknowledge on the inXuence of HPV infection on MMPexpression, and therefore progression of carcinogenesis inOSCC, is still incomplete and needs further investigations.

Conclusion

In recent years, important progress in the understanding oforopharyngeal carcinogenesis has been achieved. Extendedknowledge of the prognostic or predictive value of molecu-lar biomarkers in oropharyngeal cancer provides moreinsight into carcinogenesis and can, therefore, improve andspecify diagnosis, tumor classiWcations, therapy andappraisal of clinical outcome in OSCC.

Declaration of HPV status in OSCC, using immunohis-tochemical staining of p16 and PCR of HPV-DNA, forexample, presents a reliable prognostic and predictivemarker. Recently published studies indicate that HPV/p16associated carcinomas present a better response to induc-tion chemotherapy and a better prognosis after deWniteradiochemotherapy [29, 128]. These results indicated thatthe possibility of a reliable selection of patients for individ-ualized therapy depended on the HPV status of theirtumors. However, more prospective, possibly collaborativestudies incorporating a reliable quality of samples from auniform anatomic site, standardization of the analysis meth-ods and synchronic curative protocols are warranted to fur-ther improve the clinical validation of biomarkers and theiruse for tailored treatment strategies in patients with OSCC.

References

1. Altieri DC (2003) Validating survivin as a cancer therapeutictarget. Nat Rev Cancer 3:46–54

123


2. Andl T, Kahn T, Pfuhl A, Nicola T, Erber R, Conradt C, Klein W,Helbig M, Dietz A, Weidauer H, Bosch FX (1998) Etiologicalinvolvement of oncogenic human papillomavirus in tonsillarsquamous cell carcinomas lacking retinoblastoma cell cycle con-trol. Cancer Res 58:5–13

3. Begum S, Cao D, Gillison M, Zahurak M, Westra WH (2005)Tissue distribution of human papillomavirus 16 DNA integrationin patients with tonsillar carcinoma. Clin Cancer Res 11:5694–5699

4. Birchmeier W, Behrens J (1994) Cadherin expression in carcino-mas: role in the formation of cell junctions and the prevention ofinvasiveness. Biochim Biophys Acta 1198:11–26

5. Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB,Jones CU, Sur R, Raben D, Jassem J, Ove R, Kies MS, BaselgaJ, YoussouWan H, Amellal N, Rowinsky EK, Ang KK (2006)Radiotherapy plus cetuximab for squamous-cell carcinoma of thehead and neck. N Engl J Med 354:567–578

6. Borbely AA, Murvai M, Konya J, Beck Z, Gergely L, Li F,Veress G (2006) EVects of human papillomavirus type 16 onco-proteins on survivin gene expression. J Gen Virol 87:287–294

7. Bos JL (1989) ras oncogenes in human cancer: a review. CancerRes 49:4682–4689

8. Brabender J, Vallbohmer D, Grimminger P, HoVmann AC, LingF, Lurje G, Bollschweiler E, Schneider PM, Holscher AH,Metzger R (2008) ERCC1 RNA expression in peripheral bloodpredicts minor histopathological response to neoadjuvant radio-chemotherapy in patients with locally advanced cancer of theesophagus. J Gastrointest Surg 12:1815–1821

9. Branca M, Ciotti M, Giorgi C, Santini D, Di Bonito L, Costa S,Benedetto A, Bonifacio D, Di Bonito P, Paba P, Accardi L,Syrjanen S, Favalli C, Syrjanen K (2008) Predicting high-riskhuman papillomavirus infection, progression of cervical intraep-ithelial neoplasia, and prognosis of cervical cancer with a panelof 13 biomarkers tested in multivariate modeling. Int J GynecolPathol 27:265–273

10. Brocic M, Kozomara R, Cerovic S, Jovic N, Vukelic-MarkovicS, Stosic S (2009) Clinical signiWcance of vascular endothelialgrowth factor expression in patients with carcinoma of the mouthXoor and tongue. Vojnosanit Pregl 66:440–448

11. Bromberg J, Darnell JE Jr (2000) The role of STATs in transcrip-tional control and their impact on cellular function. Oncogene19:2468–2473

12. Caamano J, Zhang SY, Rosvold EA, Bauer B, Klein-Szanto AJ(1993) p53 alterations in human squamous cell carcinomas andcarcinoma cell lines. Am J Pathol 142:1131–1139

13. Califano J, van der Riet P, Westra W, Nawroz H, Clayman G,Piantadosi S, Corio R, Lee D, Greenberg B, Koch W, SidranskyD (1996) Genetic progression model for head and neck cancer:implications for Weld cancerization. Cancer Res 56:2488–2492

14. Camisasca DR, Honorato J, Bernardo V, da Silva LE, da FonsecaEC, de Faria PA, Dias FL, Lourenco Sde Q (2009) Expression ofBcl-2 family proteins and associated clinicopathologic factorspredict survival outcome in patients with oral squamous cell car-cinoma. Oral Oncol 45:225–233

15. Carvalho AL, Nishimoto IN, Califano JA, Kowalski LP (2005)Trends in incidence and prognosis for head and neck cancer in theUnited States: a site-speciWc analysis of the SEER database. Int JCancer 114:806–816

16. Catlett-Falcone R, Dalton WS, Jove R (1999) STAT proteins asnovel targets for cancer therapy. Signal transducer an activator oftranscription. Curr Opin Oncol 11:490–496

17. Cavalot A, Martone T, Roggero N, Brondino G, Pagano M,Cortesina G (2007) Prognostic impact of HER-2/neu expressionon squamous head and neck carcinomas. Head Neck 29:655–664

18. Chen HH, Yu CH, Wang JT, Liu BY, Wang YP, Sun A, Tsai TC,Chiang CP (2007) Expression of human telomerase reverse trans-

criptase (hTERT) protein is signiWcantly associated with the pro-gression, recurrence and prognosis of oral squamous cellcarcinoma in Taiwan. Oral Oncol 43:122–129

19. Chin L, Tam A, Pomerantz J, Wong M, Holash J, Bardeesy N,Shen Q, O’Hagan R, Pantginis J, Zhou H, Horner JW 2nd, Cordon-Cardo C, Yancopoulos GD, DePinho RA (1999) Essential role foroncogenic Ras in tumour maintenance. Nature 400:468–472

20. Cobo M, Isla D, Massuti B, Montes A, Sanchez JM, Provencio M,Vinolas N, Paz-Ares L, Lopez-Vivanco G, Munoz MA, Felip E,Alberola V, Camps C, Domine M, Sanchez JJ, Sanchez-Ronco M,Danenberg K, Taron M, Gandara D, Rosell R (2007) Customizingcisplatin based on quantitative excision repair cross-complementing1 mRNA expression: a phase III trial in non-small-cell lungcancer. J Clin Oncol 25:2747–2754

21. Cully M, You H, Levine AJ, Mak TW (2006) Beyond PTENmutations: the PI3K pathway as an integrator of multiple inputsduring tumorigenesis. Nat Rev Cancer 6:184–192

22. D’Souza G, Kreimer AR, Viscidi R, Pawlita M, Fakhry C, KochWM, Westra WH, Gillison ML (2007) Case-control study of hu-man papillomavirus and oropharyngeal cancer. N Engl J Med356:1944–1956

23. Das N, Majumder J, DasGupta UB (2000) ras gene mutations inoral cancer in eastern India. Oral Oncol 36:76–80

24. De Craene B, Gilbert B, Stove C, Bruyneel E, van Roy F, Berx G(2005) The transcription factor snail induces tumor cell invasionthrough modulation of the epithelial cell diVerentiation program.Cancer Res 65:6237–6244

25. de Vicente JC, Fresno MF, Villalain L, Vega JA, Lopez ArranzJS (2005) Immunoexpression and prognostic signiWcance ofTIMP-1 and -2 in oral squamous cell carcinoma. Oral Oncol41:568–579

26. DeClerck YA, Perez N, Shimada H, Boone TC, Langley KE,Taylor SM (1992) Inhibition of invasion and metastasis in cellstransfected with an inhibitor of metalloproteinases. Cancer Res52:701–708

27. Diniz-Freitas M, Garcia-Caballero T, Antunez-Lopez J, Gand-ara-Rey JM, Garcia-Garcia A (2006) Reduced E-cadherinexpression is an indicator of unfavourable prognosis in oral squa-mous cell carcinoma. Oral Oncol 42:190–200

28. Ensley JF, Jacobs JR, Weaver A, Kinzie J, Crissman J, Kish JA,Cummings G, Al-Sarraf M (1984) Correlation between responseto cisplatinum combination chemotherapy and subsequent radio-therapy in previously untreated patients with advanced squamouscell cancers of the head and neck. Cancer 54:811–814

29. Fakhry C, Westra WH, Li S, Cmelak A, Ridge JA, Pinto H,Forastiere A, Gillison ML (2008) Improved survival of patientswith human papillomavirus-positive head and neck squamouscell carcinoma in a prospective clinical trial. J Natl Cancer Inst100:261–269

30. Fei J, Hong A, Dobbins TA, Jones D, Lee CS, Loo C, Al-GhamdiM, Harnett GB, Clark J, O’Brien CJ, Rose B (2009) PrognosticsigniWcance of vascular endothelial growth factor in squamouscell carcinomas of the tonsil in relation to human papillomavirusstatus and epidermal growth factor receptor. Ann Surg Oncol16:2908–2917

31. Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGFand its receptors. Nat Med 9:669–676

32. Fillies T, Woltering M, Brandt B, Van Diest JP, Werkmeister R,Joos U, Buerger H (2007) Cell cycle regulating proteins p21 andp27 in prognosis of oral squamous cell carcinomas. Oncol Rep17:355–359

33. Forastiere AA (1996) Another look at induction chemotherapyfor organ preservation in patients with head and neck cancer.J Natl Cancer Inst 88:855–856

34. Giatromanolaki A, Koukourakis MI, Sivridis E, Fountzilas G(2000) c-erbB-2 oncoprotein is overexpressed in poorly vascularised

123


squamous cell carcinomas of the head and neck, but is not asso-ciated with response to cytotoxic therapy or survival. AnticancerRes 20:997–1004

35. Gillison ML (2004) Human papillomavirus-associated head andneck cancer is a distinct epidemiologic, clinical, and molecularentity. Semin Oncol 31:744–754

36. Gillison ML, Lowy DR (2004) A causal role for human papillo-mavirus in head and neck cancer. Lancet 363:1488–1489

37. Gollin SM (2001) Chromosomal alterations in squamous cell car-cinomas of the head and neck: window to the biology of disease.Head Neck 23:238–253

38. Goulart Filho JA, Nonaka CF, da Costa Miguel MC, de AlmeidaFreitas R, Galvao HC (2009) Immunoexpression of cyclooxy-genase-2 and p53 in oral squamous cell carcinoma. Am J Otolar-yngol 30:89–94

39. Grimminger PP, Schneider PM, Metzger R, Vallbohmer D,Danenberg KD, Danenberg PV, Holscher AH, Brabender J(2010) The prognostic role of Bcl-2 mRNA expression in cura-tively resected non-small cell lung cancer (NSCLC). Lung Can-cer [Epub ahaed of print]

40. Gupta S, Kong W, Peng Y, Miao Q, Mackillop WJ (2009) Tem-poral trends in the incidence and survival of cancers of the upperaerodigestive tract in Ontario and the United States. Int J Cancer125:2159–2165

41. Hafkamp HC, Mooren JJ, Claessen SM, Klingenberg B, VoogdAC, Bot FJ, Klussmann JP, Hopman AH, Manni JJ, Kremer B,Ramaekers FC, Speel EJ (2009) P21 Cip1/WAF1 expression isstrongly associated with HPV-positive tonsillar carcinoma and afavorable prognosis. Mod Pathol 22:686–698

42. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell100(1):57–70

43. Handra-Luca A, Hernandez J, Mountzios G, Taranchon E,Lacau-St-Guily J, Soria JC, Fouret P (2007) Excision repair crosscomplementation group 1 immunohistochemical expression pre-dicts objective response and cancer-speciWc survival in patientstreated by Cisplatin-based induction chemotherapy for locallyadvanced head and neck squamous cell carcinoma. Clin CancerRes 13:3855–3859

44. Hoeijmakers JH (1993) Nucleotide excision repair II: from yeastto mammals. Trends Genet 9:211–217

45. Hynes NE, Lane HA (2005) ERBB receptors and cancer: thecomplexity of targeted inhibitors. Nat Rev Cancer 5:341–354

46. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancerstatistics, 2009. CA Cancer J Clin 59:225–249

47. Jun HJ, Ahn MJ, Kim HS, Yi SY, Han J, Lee SK, Ahn YC, JeongHS, Son YI, Baek JH, Park K (2008) ERCC1 expression as a pre-dictive marker of squamous cell carcinoma of the head and necktreated with cisplatin-based concurrent chemoradiation. Br JCancer 99:167–172

48. Junttila TT, Sundvall M, Lundin M, Lundin J, Tanner M,Harkonen P, Joensuu H, Isola J, Elenius K (2005) CleavableErbB4 isoform in estrogen receptor-regulated growth of breastcancer cells. Cancer Res 65:1384–1393

49. Kapranos N, Stathopoulos GP, Manolopoulos L, Kokka E,Papadimitriou C, Bibas A, Yiotakis J, Adamopoulos G (2001)p53, p21 and p27 protein expression in head and neck cancer andtheir prognostic value. Anticancer Res 21:521–528

50. Kaur G, Carnelio S, Rao N, Rao L (2009) Expression of E-cad-herin in primary oral squamous cell carcinoma and metastaticlymph nodes: an immunohistochemical study. Indian J Dent Res20:71–76

51. Kawamata H, Uchida D, Hamano H, Kimura-Yanagawa T,Nakashiro KI, Hino S, Omotehara F, Yoshida H, Sato M (1998)Active-MMP2 in cancer cell nests of oral cancer patients: corre-lation with lymph node metastasis. Int J Oncol 13:699–704

52. Khan Z, Tiwari RP, Mulherkar R, Sah NK, Prasad GB, Shrivast-ava BR, Bisen PS (2009) Detection of survivin and p53 in humanoral cancer: correlation with clinicopathologic Wndings. HeadNeck 31:1039–1048

53. Kim SH, Koo BS, Kang S, Park K, Kim H, Lee KR, Lee MJ, KimJM, Choi EC, Cho NH (2007) HPV integration begins in the ton-sillar crypt and leads to the alteration of p16, EGFR and c-mycduring tumor formation. Int J Cancer 120:1418–1425

54. Klussmann JP, Gultekin E, Weissenborn SJ, Wieland U, Dries V,Dienes HP, Eckel HE, PWster HJ, Fuchs PG (2003) Expression ofp16 protein identiWes a distinct entity of tonsillar carcinomasassociated with human papillomavirus. Am J Pathol 162:747–753

55. Klussmann JP, Mooren JJ, Lehnen M, Claessen SM, Stenner M,Huebbers CU, Weissenborn SJ, Wedemeyer I, Preuss SF, Straet-mans JM, Manni JJ, Hopman AH, Speel EJ (2009) Genetic sig-natures of HPV-related and unrelated oropharyngeal carcinomaand their prognostic implications. Clin Cancer Res 15:1779–1786

56. Klussmann JP, Weissenborn SJ, Wieland U, Dries V, Eckel HE,PWster HJ, Fuchs PG (2003) Human papillomavirus-positive ton-sillar carcinomas: a diVerent tumor entity? Med Microbiol Immu-nol 192:129–132

57. Koh Y, Kim TM, Jeon YK, Kwon TK, Hah JH, Lee SH, KimDW, Wu HG, Rhee CS, Sung MW, Kim CW, Kim KH, Heo DS(2009) Class III beta-tubulin, but not ERCC1, is a strong predic-tive and prognostic marker in locally advanced head and necksquamous cell carcinoma. Ann Oncol 20:1414–1419

58. Kreimer AR, CliVord GM, Boyle P, Franceschi S (2005) Humanpapillomavirus types in head and neck squamous cell carcinomasworldwide: a systematic review. Cancer Epidemiol BiomarkersPrev 14:467–475

59. Kroemer G (1997) The proto-oncogene Bcl-2 and its role inregulating apoptosis. Nat Med 3:614–620

60. Kurahara S, Shinohara M, Ikebe T, Nakamura S, Beppu M,Hiraki A, Takeuchi H, Shirasuna K (1999) Expression of MMPS,MT-MMP, and TIMPs in squamous cell carcinoma of the oralcavity: correlations with tumor invasion and metastasis. HeadNeck 21:627–638

61. Kuropkat C, Plehn S, Herz U, Dunne AA, Renz H, Werner JA(2002) Tumor marker potential of serum matrix metalloprotein-ases in patients with head and neck cancer. Anticancer Res22:2221–2227

62. Kusukawa J, Sasaguri Y, Morimatsu M, Kameyama T (1995)Expression of matrix metalloproteinase-3 in stage I and II squa-mous cell carcinoma of the oral cavity. J Oral Maxillofac Surg53:530–534

63. Lebwohl D, Canetta R (1998) Clinical development of platinumcomplexes in cancer therapy: an historical perspective and anupdate. Eur J Cancer 34:1522–1534

64. Leeman RJ, Lui VW, Grandis JR (2006) STAT3 as a therapeutictarget in head and neck cancer. Expert Opin Biol Ther 6:231–241

65. Lefebvre JL (2006) Laryngeal preservation in head and neckcancer: multidisciplinary approach. Lancet Oncol 7:747–755

66. Levine AJ, Momand J, Finlay CA (1991) The p53 tumoursuppressor gene. Nature 351:453–456

67. Li F, Yang J, Ramnath N, Javle MM, Tan D (2005) Nuclear orcytoplasmic expression of survivin: what is the signiWcance? IntJ Cancer 114:509–512

68. Li Y, Nichols MA, Shay JW, Xiong Y (1994) Transcriptionalrepression of the D-type cyclin-dependent kinase inhibitor p16by the retinoblastoma susceptibility gene product pRb. CancerRes 54:6078–6082

69. Lo Muzio L, Campisi G, Giovannelli L, Ammatuna P, Greco I,Staibano S, Pannone G, De Rosa G, Di Liberto C, D’Angelo M

123


(2004) HPV DNA and survivin expression in epithelial oral car-cinogenesis: a relationship? Oral Oncol 40:736–741

70. Lo Muzio L, Falaschini S, Farina A, Rubini C, Pezzetti F, Camp-isi G, De Rosa G, Capogreco M, Carinci F (2005) Bcl-2 as prog-nostic factor in head and neck squamous cell carcinoma. OncolRes 15:249–255

71. Lord RV, Brabender J, Gandara D, Alberola V, Camps C,Domine M, Cardenal F, Sanchez JM, Gumerlock PH, Taron M,Sanchez JJ, Danenberg KD, Danenberg PV, Rosell R (2002) LowERCC1 expression correlates with prolonged survival aftercisplatin plus gemcitabine chemotherapy in non-small cell lungcancer. Clin Cancer Res 8:2286–2291

72. Lu XZ, Zou YG, Yin XM, Chen WT, Zhang CP (2008) Expres-sion of MMP1 mRNA in oral squamous cell carcinoma andpaired normal tissues. Nan Fang Yi Ke Da Xue Xue Bao28:1362–1364

73. Mahomed F, Altini M, Meer S (2007) Altered E-cadherin/beta-catenin expression in oral squamous carcinoma with and withoutnodal metastasis. Oral Dis 13:386–392

74. Mandriota SJ, Jussila L, Jeltsch M, Compagni A, Baetens D,Prevo R, Banerji S, Huarte J, Montesano R, Jackson DG, Orci L,Alitalo K, Christofori G, Pepper MS (2001) Vascular endothelialgrowth factor-C-mediated lymphangiogenesis promotes tumourmetastasis. EMBO J 20:672–682

75. Manning FC, Patierno SR (1996) Apoptosis: inhibitor or instiga-tor of carcinogenesis? Cancer Invest 14:455–465

76. Mao L, Hong WK, Papadimitrakopoulou VA (2004) Focus onhead and neck cancer. Cancer Cell 5:311–316

77. Masuda M, Suzui M, Yasumatu R, Nakashima T, Kuratomi Y,Azuma K, Tomita K, Komiyama S, Weinstein IB (2002) Consti-tutive activation of signal transducers and activators of transcrip-tion 3 correlates with cyclin D1 overexpression and may providea novel prognostic marker in head and neck squamous cell carci-noma. Cancer Res 62:3351–3355

78. Mineta H, Miura K, Takebayashi S, Ueda Y, Misawa K, HaradaH, Wennerberg J, Dictor M (2000) Cyclin D1 overexpressioncorrelates with poor prognosis in patients with tongue squamouscell carcinoma. Oral Oncol 36:194–198

79. Miyamoto R, Uzawa N, Nagaoka S, Hirata Y, Amagasa T (2003)Prognostic signiWcance of cyclin D1 ampliWcation and overex-pression in oral squamous cell carcinomas. Oral Oncol 39:610–618

80. Murray D, Rosenberg E (1996) The importance of the ERCC1/ERCC4[XPF] complex for hypoxic-cell radioresistance does notappear to derive from its participation in the nucleotide excisionrepair pathway. Mutat Res 364:217–226

81. Murugan AK, Hong NT, Cuc TT, Hung NC, Munirajan AK,Ikeda MA, Tsuchida N (2009) Detection of two novel mutationsand relatively high incidence of H-RAS mutations in Vietnameseoral cancer. Oral Oncol 45:e161–e166

82. Nagpal JK, Patnaik S, Das BR (2002) Prevalence of high-riskhuman papilloma virus types and its association with P53 codon72 polymorphism in tobacco addicted oral squamous cell carci-noma (OSCC) patients of Eastern India. Int J Cancer 97:649–653

83. Nakanishi C, Toi M (2005) Nuclear factor-kappaB inhibitors assensitizers to anticancer drugs. Nat Rev Cancer 5:297–309

84. Olaussen KA, Dunant A, Fouret P, Brambilla E, Andre F,Haddad V, Taranchon E, Filipits M, Pirker R, Popper HH, StahelR, Sabatier L, Pignon JP, Tursz T, Le Chevalier T, Soria JC(2006) DNA repair by ERCC1 in non-small-cell lung cancer andcisplatin-based adjuvant chemotherapy. N Engl J Med 355:983–991

85. Pannone G, Sanguedolce F, De Maria S, Farina E, Lo Muzio L,Serpico R, Emanuelli M, Rubini C, De Rosa G, Staibano S,Macchia L, Bufo P (2007) Cyclooxygenase isozymes in oralsquamous cell carcinoma: a real-time RT-PCR study with clinic

pathological correlations. Int J Immunopathol Pharmacol20:317–324

86. Peinado H, Portillo F, Cano A (2004) Transcriptional regulationof cadherins during development and carcinogenesis. Int J DevBiol 48:365–375

87. Polkowski W, van Sandick JW, OVerhaus GJ, ten Kate FJ,Mulder J, Obertop H, van Lanschot JJ (1999) Prognostic value ofLauren classiWcation and c-erbB-2 oncogene overexpression inadenocarcinoma of the esophagus and gastroesophageal junction.Ann Surg Oncol 6:290–297

88. Preuss SF, Weinell A, Molitor M, Semrau R, Stenner M, DrebberU, Wedemeyer I, HoVmann TK, Guntinas-Lichius O, KlussmannJP (2008) Survivin and epidermal growth factor receptor expres-sion in surgically treated oropharyngeal squamous cell carci-noma. Head Neck 30:1318–1324

89. Preuss SF, Weinell A, Molitor M, Stenner M, Semrau R, DrebberU, Weissenborn SJ, Speel EJ, Wittekindt C, Guntinas-Lichius O,HoVmann TK, Eslick GD, Klussmann JP (2008) Nuclear survi-vin expression is associated with HPV-independent carcinogene-sis and is an indicator of poor prognosis in oropharyngeal cancer.Br J Cancer 98:627–632

90. Ragin CC, Taioli E (2007) Survival of squamous cell carcinomaof the head and neck in relation to human papillomavirus infec-tion: review and meta-analysis. Int J Cancer 121:1813–1820

91. Ravi D, Ramadas K, Mathew BS, Nalinakumari KR, Nair MK,Pillai MR (1999) De novo programmed cell death in oral cancer.Histopathology 34:241–249

92. Reed E (2005) ERCC1 and clinical resistance to platinum-basedtherapy. Clin Cancer Res 11:6100–6102

93. Reimers N, Kasper HU, Weissenborn SJ, Stutzer H, Preuss SF,HoVmann TK, Speel EJ, Dienes HP, PWster HJ, Guntinas-LichiusO, Klussmann JP (2007) Combined analysis of HPV-DNA, p16and EGFR expression to predict prognosis in oropharyngeal can-cer. Int J Cancer 120:1731–1738

94. Reuter CW, Morgan MA, Eckardt A (2007) Targeting EGF-receptor-signalling in squamous cell carcinomas of the head andneck. Br J Cancer 96:408–416

95. Roberts PJ, Der CJ (2007) Targeting the Raf-MEK-ERK mito-gen-activated protein kinase cascade for the treatment of cancer.Oncogene 26:3291–3310

96. Rogers SJ, Harrington KJ, Rhys-Evans P, OC P, Eccles SA(2005) Biological signiWcance of c-erbB family oncogenes inhead and neck cancer. Cancer Metastasis Rev 24:47–69

97. Roskoski R Jr (2004) The ErbB/HER receptor protein-tyrosinekinases and cancer. Biochem Biophys Res Commun 319:1–11

98. Rozenblum E, Schutte M, Goggins M, Hahn SA, Panzer S,Zahurak M, Goodman SN, Sohn TA, Hruban RH, Yeo CJ,Kern SE (1997) Tumor-suppressive pathways in pancreaticcarcinoma. Cancer Res 57:1731–1734

99. Salven P, Heikkila P, Anttonen A, Kajanti M, Joensuu H (1997)Vascular endothelial growth factor in squamous cell head andneck carcinoma: expression and prognostic signiWcance. ModPathol 10:1128–1133

100. Samuels Y, Velculescu VE (2004) Oncogenic mutations ofPIK3CA in human cancers. Cell Cycle 3:1221–1224

101. Sappayatosok K, Maneerat Y, Swasdison S, Viriyavejakul P,Dhanuthai K, Zwang J, Chaisri U (2009) Expression of pro-inXammatory protein, iNOS, VEGF and COX-2 in oral squa-mous cell carcinoma (OSCC), relationship with angiogenesis andtheir clinico-pathological correlation. Med Oral Patol Oral CirBucal 14:E319–E324

102. Serrano M, Hannon GJ, Beach D (1993) A new regulatory motifin cell-cycle control causing speciWc inhibition of cyclinD/CDK4. Nature 366:704–707

103. Sherr CJ, Roberts JM (1995) Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev 9:1149–1163

123


104. Sheu JJ, Hua CH, Wan L, Lin YJ, Lai MT, Tseng HC, JinawathN, Tsai MH, Chang NW, Lin CF, Lin CC, Hsieh LJ, Wang TL,Shih Ie M, Tsai FJ (2009) Functional genomic analysis identiWedepidermal growth factor receptor activation as the most commongenetic event in oral squamous cell carcinoma. Cancer Res69:2568–2576

105. Shiboski CH, Schmidt BL, Jordan RC (2005) Tongue and tonsilcarcinoma: increasing trends in the US population ages 20–44 years. Cancer 103:1843–1849

106. Shiga H, Rasmussen AA, Johnston PG, Langmacher M, BaylorA, Lee M, Cullen KJ (2000) Prognostic value of c-erbB2 and oth-er markers in patients treated with chemotherapy for recurrenthead and neck cancer. Head Neck 22:599–608

107. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V,Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M,Baselga J, Norton L (2001) Use of chemotherapy plus a monoclo-nal antibody against HER2 for metastatic breast cancer that over-expresses HER2. N Engl J Med 344:783–792

108. Smeets SJ, Hesselink AT, Speel EJ, Haesevoets A, Snijders PJ,Pawlita M, Meijer CJ, Braakhuis BJ, Leemans CR, BrakenhoVRH (2007) A novel algorithm for reliable detection of humanpapillomavirus in paraYn embedded head and neck cancer spec-imen. Int J Cancer 121:2465–2472

109. Smith BD, Smith GL, Carter D, Sasaki CT, HaVty BG (2000)Prognostic signiWcance of vascular endothelial growth factor pro-tein levels in oral and oropharyngeal squamous cell carcinoma.J Clin Oncol 18:2046–2052

110. Steinbach G, Lynch PM, Phillips RK, Wallace MH, Hawk E,Gordon GB, Wakabayashi N, Saunders B, Shen Y, Fujimura T,Su LK, Levin B (2000) The eVect of celecoxib, a cyclooxygen-ase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med342:1946–1952

111. Stewart SA, Weinberg RA (2000) Telomerase and human tumor-igenesis. Semin Cancer Biol 10:399–406

112. Su JL, Yang PC, Shih JY, Yang CY, Wei LH, Hsieh CY, ChouCH, Jeng YM, Wang MY, Chang KJ, Hung MC, Kuo ML (2006)The VEGF-C/Flt-4 axis promotes invasion and metastasis of can-cer cells. Cancer Cell 9:209–223

113. Syrjanen S (2007) Human papillomaviruses in head and neck car-cinomas. N Engl J Med 356:1993–1995

114. Takatori H, Natsugoe S, Okumura H, Matsumoto M, UchikadoY, Setoyama T, Sasaki K, Tamotsu K, Owaki T, Ishigami S,Aikou T (2008) Cyclooxygenase-2 expression is related to prog-nosis in patients with esophageal squamous cell carcinoma. Eur JSurg Oncol 34:397–402

115. Tanigaki Y, Nagashima Y, Kitamura Y, Matsuda H, Mikami Y,Tsukuda M (2004) The expression of vascular endothelial growthfactor-A and -C, and receptors 1 and 3: correlation with lymphnode metastasis and prognosis in tongue squamous cell carci-noma. Int J Mol Med 14:389–395

116. Temam S, Flahault A, Perie S, Monceaux G, Coulet F, Callard P,Bernaudin JF, St Guily JL, Fouret P (2000) p53 gene status as apredictor of tumor response to induction chemotherapy of pa-tients with locoregionally advanced squamous cell carcinomas ofthe head and neck. J Clin Oncol 18:385–394

117. Thiery JP, Sleeman JP (2006) Complex networks orchestrate epi-thelial–mesenchymal transitions. Nat Rev Mol Cell Biol 7:131–142

118. Vallbohmer D, Brabender J, Metzger R, Holscher AH (2009)Genetics in the pathogenesis of esophageal cancer: possiblepredictive and prognostic factors. J Gastrointest Surg

119. Vivanco I, Palaskas N, Tran C, Finn SP, Getz G, Kennedy NJ,Jiao J, Rose J, Xie W, Loda M, Golub T, MellinghoV IK, DavisRJ, Wu H, Sawyers CL (2007) IdentiWcation of the JNK signalingpathway as a functional target of the tumor suppressor PTEN.Cancer Cell 11:555–569

120. Vonderheide RH, Hahn WC, Schultze JL, Nadler LM (1999) Thetelomerase catalytic subunit is a widely expressed tumor-associ-ated antigen recognized by cytotoxic T lymphocytes. Immunity10:673–679

121. Waldman T, Lengauer C, Kinzler KW, Vogelstein B (1996)Uncoupling of S phase and mitosis induced by anticancer agentsin cells lacking p21. Nature 381:713–716

122. Weber A, Langhanki L, Sommerer F, Markwarth A, Wittekind C,Tannapfel A (2003) Mutations of the BRAF gene in squamouscell carcinoma of the head and neck. Oncogene 22:4757–4759

123. Werkmeister R, Brandt B, Joos U (2000) Clinical relevance oferbB-1 and -2 oncogenes in oral carcinomas. Oral Oncol 36:100–105

124. Williams GT (1991) Programmed cell death: apoptosis and onco-genesis. Cell 65:1097–1098

125. Wilson GD, Saunders MI, Dische S, Richman PI, Daley FM,Bentzen SM (2001) bcl-2 expression in head and neck cancer: anenigmatic prognostic marker. Int J Radiat Oncol Biol Phys49:435–441

126. Wittekindt C, Gultekin E, Weissenborn SJ, Dienes HP, PWsterHJ, Klussmann JP (2005) Expression of p16 protein is associatedwith human papillomavirus status in tonsillar carcinomas and hasimplications on survival. Adv Otorhinolaryngol 62:72–80

127. Witton CJ, Reeves JR, Going JJ, Cooke TG, Bartlett JM (2003)Expression of the HER1–4 family of receptor tyrosine kinases inbreast cancer. J Pathol 200:290–297

128. Worden FP, Kumar B, Lee JS, Wolf GT, Cordell KG, Taylor JM,Urba SG, Eisbruch A, Teknos TN, Chepeha DB, Prince ME,Tsien CI, D’Silva NJ, Yang K, Kurnit DM, Mason HL, MillerTH, Wallace NE, Bradford CR, Carey TE (2008) Chemoselec-tion as a strategy for organ preservation in advanced oropharynxcancer: response and survival positively associated with HPV16copy number. J Clin Oncol 26:3138–3146

129. Wouters BG, Giaccia AJ, Denko NC, Brown JM (1997) Loss ofp21Waf1/Cip1 sensitizes tumors to radiation by an apoptosis-independent mechanism. Cancer Res 57:4703–4706

130. Xie X, Clausen OP, Boysen M (2002) Prognostic signiWcance ofp21WAF1/CIP1 expression in tongue squamous cell carcinomas.Arch Otolaryngol Head Neck Surg 128:897–902

131. Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D(1993) p21 is a universal inhibitor of cyclin kinases. Nature366:701–704

132. Yamamoto T, Tanigawa N (2001) The role of survivin as a newtarget of diagnosis and treatment in human cancer. Med ElectronMicrosc 34:207–212

133. Yorioka CW, Coletta RD, Alves F, Nishimoto IN, Kowalski LP,Graner E (2002) Matrix metalloproteinase-2 and -9 activities cor-relate with the disease-free survival of oral squamous cell carci-noma patients. Int J Oncol 20:189–194

134. Zhang M, Zhang P, Zhang C, Sun J, Wang L, Li J, Tian Z, ChenW (2009) Prognostic signiWcance of Bcl-2 and Bax proteinexpression in the patients with oral squamous cell carcinoma.J Oral Pathol Med 38:307–313

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